The critically ill patient frequently develops a complex disease spectrum that includes sepsis syndrome and/or septic shock. A major cause of delayed deaths in the critically ill patient is multiple organ dysfunction syndrome (MODS). Current knowledge suggests that MODS is related to dysregulation of innate immunity which can involve a hyperinflammatory shock like state resulting in disseminated tissue injury as well as a prolong immune suppression that can predispose to opportunistic infections. The presence of myocardial dysfunction in patients with sepsis/septic shock/MODS is well known. Recent evidence indicates that the innate immune response plays a central role in the pathophysiology of cardiac dysfunction in sepsis/septic shock. However, the mechanisms by which innate immunity mediates cardiac dysfunction are only now coming to the light. Furthermore, the physiologic mechanisms that attempt to limit the inflammatory response, promote survival of cardiac myocytes, and maintain cardiovascular homeostasis in sepsis/septic shock remain unclear. Toll-like receptor (TLR)-mediated signaling plays a critical role in the induction of innate and inflammatory responses. Our preliminary data indicate that TLR2 and TLR4 have strikingly different and opposing, i.e. differential, effects on cardiac function during sepsis/septic shock. Our data also suggest that modulation of TLR2/TLR4-dependent signaling pathways may be an effective approach for preventing/managing cardiac dysfunction in sepsis/septic shock. The experiments outlined in this application will test the hypothesis that differential modulation of TLR2 and TLR4 signaling pathways determine the fate of cardiac function in response to sepsis/septic shock insult. To test this hypothesis, we will pursue three specific aims. 1. We will elucidate the mechanisms by which TLR4 deficiency attenuates cardiac dysfunction in sepsis/septic shock 2. We will define the mechanisms by which modulation of TLR2 improves cardiac function in sepsis/septic shock. 3. We will investigate whether differential regulation of TLR2/4 and PI3K/Akt signaling pathways has an additive effect on cardioprotection during sepsis/septic shock. These studies will provide a mechanistic understanding of the signaling pathways that are critical for myocardial function and/or dysfunction in sepsis. It may also be possible to apply this knowledge in a practical fashion to identify new and novel therapeutic approaches to prevent or manage cardiac dysfunction in sepsis/septic shock. PUBLIC HEALTH RELEVANCE: The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock and multiple organ dysfunction syndrome (MODS). In the United States ~750,000 patients/year develop sepsis syndrome. Of these patients, the overall mortality rate is 28.6% (~215,000 deaths/year). Those patients that survive the initial event, which may include trauma, may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due immune dysfunction and infection. Indeed, sepsis is a frequent cause of MODS. It is well known that cardiovascular dysfunction is also associated with MODS morbidity and mortality. Attempts at developing effective therapies for sepsis/septic shock and MODS has proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and molecular mechanisms that mediate cardiac dysfunction in sepsis. Thus, it is clear that a better understanding of the molecular mechanisms leading to cardiac dysfunction during sepsis/septic shock is essential in developing adjunctive therapies that could decrease both morbidity and mortality. These studies will provide a mechanistic understanding of the cellular signaling pathways that are critical for myocardial function and/or dysfunction in sepsis. It may also be possible to apply this knowledge in a practical fashion to identify new and novel therapeutic approaches to prevent or manage cardiac dysfunction in sepsis/septic shock.